Dr Strijbos meets Prof Powles: EV-302/KEYNOTE-A39

This year’s ESMO marked a significant milestone in bladder cancer research. Prof Thomas Powles from Barts Cancer Centre in London, UK, unveiled revolutionary data that is poised to significantly alter how we manage urothelial cancer. Dr Michiel Strijbos, a GU oncologist at GZA Wilrijk, seized the opportunity to converse with prof Powles about these groundbreaking outcomes.

Background

Platinum-based chemotherapy has been the cornerstone of first-line treatment for patients with locally advanced or metastatic urothelial carcinoma for a long time. However, the prognosis for these patients continues to be disappointing, regardless of the type of initial treatment. The pursuit to improve these outcomes has given rise to multiple attempts to introduce therapies that could potentially outperform chemotherapy, but until now, these have unfortunately not been successful. At the presidential session at this year’s ESMO, a groundbreaking development occurred. For the first time ever, data was presented that showcased a treatment outdoing platinum-based chemotherapy in terms of overall survival for patients with previously untreated locally advanced or metastatic urothelial carcinoma. This is a significant advancement in bladder cancer treatment and a beacon of hope for patients.

Enfortumab vedotin (EV) and pembrolizumab (P) are two drugs that have independently demonstrated survival benefits in the treatment of previously treated locally advanced/metastatic urothelial carcinoma. EV is a Nectin-4 directed antibody-drug conjugate. It specifically targets Nectin-4, a protein that is overexpressed in urothelial carcinomas. This targeted approach allows the drug to deliver a potent cytotoxic agent directly to cancer cells, sparing healthy cells and potentially reducing side effects. The targeted approach of EV combined with the immune-enhancing effect of P might lead to a synergistic effect, potentially leading to better survival outcomes than either drug alone.

Trial Design

Prof Powles summarised the objective and outcomes of the EV-302/KEYNOTE-A39 trial. The combination of EV + P was compared to platinum-based chemotherapy in previously untreated patients with locally advanced or metastatic urothelial carcinoma, regardless of cisplatin eligibility and PD-L1 expression status. Patients were assigned in a 1:1 ratio, categorized by cisplatin eligibility, PD-L1 expression and the presence or absence of liver metastases, to EV + P versus gemcitabine + cisplatin or carboplatin. Progression-free survival was significantly improved in the EV + P arm with an increase from a median of 6.3 months to 12.5 months (HR: 0.45, 95% CI: 0.38 – 0.45, p<0.001). Overall survival was nearly double in the EV + P arm, with median survivals of 31.5 and 16.1 months in the EV + P and chemotherapy arms, respectively (HR: 0.47, 95% CI: 0.38 – 0.58, p<0.00001). The benefits in pre-specified subgroups and stratification factors were consistent with those observed in the overall population. The most common treatment-related adverse events associated with EV were skin reactions, peripheral neuropathy, ocular disorders and hyperglycemia, which are generally manageable. There were four treatment-related deaths in both arms (0.9%). However, the lack of consistency among these cases suggests that the causes were likely diverse and not directly tied to the treatment.

Clinical Practice

Dr Strijbos and prof Powles concluded that EV + P will become the new standard of care for first-line treatment of locally advanced or metastatic urothelial carcinoma. They also briefly touched upon the CheckMate 901 trial, also presented during the presidential symposium. showing that the combination of nivolumab with gemcitabine/cisplatin, improved overall survival for patients with unresectable or metastatic urothelial carcinoma. The combined use of nivolumab and gemcitabine/cisplatin is another significant breakthrough in the treatment of unresectable or metastatic urothelial carcinoma. According to both experts, this combination can be a promising alternative for patients who are not able to receive the EV + P combination.